虎杖苷RGD三肽/叶酸双靶向MSNs载药系统的构建及其抑制RA免疫炎性代谢性损伤的应用基础研究

The pathological causes of rheumatoid arthritis (RA) are complicated, and current treatment however lack of efficient medicines with low side effects.There is an urgent need to explore novel medications. Comparing with traditional medications, medicine conjugated with nanocarrier based drug delivery system is characterized with high specificity, slow-releasing capacity and high drug concentration in target tissue with low off-target effeciency.Most nanocarriers used to treat RA are macro-molecules and organic material.However,the overall efficient of these kinds of nanomedicine are not as good as expected because of the stability of those carrier, which are easily to be degraded by hydrolases and absorbed by endothelium reticular cells. Mesoporous silica nanoparticles (MSNs) is a unique bio-material with high biocompatibility and structure stability, and it is easily to be modified. Therefore, we propose to to use APTs-modified MSNs as a nanocarrier. Meanwhile,folic acid (FA) and RGD tripeptideis used to target inflammatory infiltrated cells in RA. We aim to design a novel bi-target drug delivery system by conjugating MSNs with RGD tripeptide and FA to enhance the specificity of drug delivery. Our previous study indicated that polydatin(TMTI) couldreduce the injury caused by inflammatory and metabolic disorders in RA, mainly through regulating inflammatory cells. We aim to deliver polydatin by the nanocarriercomplex of MSNs/RGD tripeptide/FA through i.v.injection to treat RA. Our study will provide evidence to develop novel strategy for RA treatment and safe and effective nanocarrier based drug delivery system for traditional Chinese medication.

类风湿关节炎（RA）病机复杂，但是目前临床药物少缺且药毒性大，急需研发新型药物／剂型。纳米靶向药物定向输送，逐步释放，增加选择性原位富集，避免非靶区毒性损害，解决了传统药的弊端。然而研究的主流集中于大分子、有机材料，因其易被水解酶破坏，被网状内皮系统摄取和清除等缺点，同样影响靶向制剂的生物学效应。而基于良好生物相容性，易修饰，易改性，骨架结构稳定的介孔二氧化硅粒子（MSNs）在生物材料中独具特色。本课题结合RA的靶向特异性，设计APTS修饰的MSNs，突破目前叶酸（FA）单独靶向和RGD三肽单独靶向研究模式，合成新型RGD三肽/FA双靶向MSNs载体。拟以我们前期研究显示对RA滑膜免疫炎性代谢性损伤有显著抑制作用的虎杖苷（TMT1）为模型药，偶联RGD三肽/FA双靶向MSNs载体，研制靶向RA的静脉给药剂型，从而为探讨治疗RA的新方法和安全有效的中药纳米靶向载药体系提供实验支持。

RA的发病与免疫炎性代谢诸因素相关，机制复杂，治疗药物少缺且药物毒性大，对其发病机制及治疗对策的研究是国际医学领域的热点。纳米靶向药具有定向输送，选择性原位富集的优势，基于良好生物相容性，易修饰，易改性，骨架结构稳定的MSNs在生物材料中独具特色。本课题结合RA的靶向特异性，以前期研究对RA滑膜免疫炎性代谢性损伤有显著抑制作用的虎杖苷为模型药，设计了偶联RGD三肽/FA双靶向MSNs载药体系，并完成系列表征论证及生物安全性评价，结果显示在规定浓度、剂量下无明显毒副作用。体内实验证明，显著改善CIA模型大鼠踝关节炎性肿胀程度、及膝关节滑膜炎性病理损伤。本研究在完成任务书计划项目的基础上，增加了CIA大鼠膝关节滑膜组织的转录组学及关节滑液代谢组学检测，增加了RA兔关节滑膜成纤维细胞的蛋白组学检测，结合前期分子机制研究，对纳米载药体系干预CIA模型大鼠关节滑膜区域免疫炎性代谢性损伤的关键分子p38MAPK信号通路进行了体内外模型的mRNA转录水平及蛋白水平的探讨，研究发现纳米载体药通过调节GABA-p38MAPK-MRTF/SRF信号通路抑制RA关节滑膜免疫炎性代谢损伤，为后续研究奠定了基础。